Using non-covalent interactions to direct regioselective 2+2 photocycloaddition within a macrocyclic cavitand

Article abstract of DOI:10.1039/c5nj02376a

The relative orientation of guests within ternary inclusion complexes is governed by the host-guest and guest-guest supramolecular interactions. Selectivity in 2+2 photocycloaddition between two alkenes included within a macrocyclic cavitand (γ-cyclodextrin) can be controlled using non-covalent interactions. In this manuscript, we report cavitand-mediated control of regioselectivity between alkyl cinnamates using non-covalent interactions. Using this method, we have shown that regioselectivity can be switched completely from a head-to-head dimer to a head-to-tail dimer. The reactions were also stereoselective in most cases. Stoichiometry experiments were performed to explore relative stabilities of the complexes, which indicate that the ternary complex is more stable than others. Selectivity in the photocycloaddition reaction was also applied retrospectively to deduce intermolecular orientations. Time-dependent conversion study we performed indicates that the observed reactivity of alkenes is representative of the intermolecular orientations in the bulk of the complex medium. Experimental observations and computational studies were used to qualitatively understand the complex structures, and relative magnitudes of the weak interactions. The reactions of complexes were studied in slurry form, and the extent of reaction control suggests a solid-state-like behavior.

Full text of DOI:10.1039/c5nj02376a

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Using non-covalent interactions to direct regioselective 2+2 photocycloaddition
within macrocyclic cavitand
Nga Nguyen, Aspen Rae Clements, and Mahesh Pattabiraman*
ABSTRACT
The relative orientation of guests within ternary inclusion complexes is governed by the host-guest
and guest-guest supramolecular interactions. Selectivity in 2+2 photocycloaddition between two alkenes
included within macrocyclic cavitand (γ-cyclodextrin) can be controlled using non-covalent interactions. In
this manuscript we report caviand-mediated control of regioselectivity between alkyl cinnamates using non-
covalent interactions. Using this method, we have shown that regioselectivity can be switched completely
from a head-to-head dimer to head-to-tail dimer. The reactions were also stereoselective in most cases.
Stoichiometry experiments were performed to explore relative stabilities of the complexes, which indicate
that the ternary complex is more stable than others. Selectivity in the photocycloaddition reaction was also
applied retrospectively to deduce intermolecular orientations. Time-dependent conversion study indicate
that the observed reactivity of the alkenes is representative of the intermolecular orientations in the bulk of
the complex medium. Experimental observations and computational studies were used to qualitatively
understand the complex structures, and relative magnitudes of the weak interactions. The reactions of
complexes were studied in slurry form, and extent of reaction control suggests a solid-state like behavior.
INTRODUCTION
Photocycloaddition is a well-studied bimolecular photoreaction.1 Application of this reaction in the
fields of materials science,2-4 organic synthesis,5-7 and optical data storage,8-10 makes it a highly useful
reactions. Photocycloaddition between the nucleic bases is an important reaction relevant to cell biology.11-
13 Moreover, stereospecific cyclobutane cores are found in a number of natural compounds with biological
and medicinal significance.14 Given its importance, controlling reaction efficiency and selectivity will have
practical value. The 2+2 photocycloaddition of alkene can give rise to four different isomeric dimers (scheme
1),15-17 As a simple addition reaction between π-bonded carbons, the shape of the isomer is structurally
close to the arrangement of the alkenes prior to reaction, a term referred to as ‘molecular memory’.18-21 This
has proved to be a valuable tool in the hands of supramolecular chemists for deducing effects of weak
interactions in molecular self-assembly. Photoactive alkenes with weakly interacting groups were allowed
to self-assemble, whose photoreactivity and chemo- and/or stereoselectivities were used to predict
influence of weak interactions. Starting with Schmidt’s topochemical studies of cinnamic acids, several
examples are known, where the effects of weak interaction such as π-π,22 CH-π,23, 24 charge-transfer,18, 25,
26
weak hydrogen bonding,27 and halo-halo,18, 28 have been studied through their manifested reaction
selectivities. While this approach has been predominantly studied in the crystalline-state, it has also been
implemented using host-guest chemistry. The proximity between guest molecules entrapped within the
limited spaces of cavitands (host) facilitate intermolecular interactions. Host-guest chemists have used such
reaction selectivity to study directing effects of weak interactions in the complexes.29-35 In this manuscript
we report the directing influences and relative magnitudes of steric, π-π, and halo..halo interactions
deduced through photochemical reactivity of γ-cyclodextrin (γ–CD) complexes of alkyl cinnamates.

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Scheme 1. Photoproducts resulting from the excited state reactivity of alkyl cinnamates.
Cavitand-mediated photodimerization of alkenes has been known since the early 1980s when
Tanaka et al reported the influence of β-cyclodextrin on the photodimerization of coumarins.36 Leading
supramolecular chemistry groups have utilized this strategy to control the stereo- and regioselectivities of
bimolecular photoreactions.37-39 In this manuscript we report our ability to control the regiochemistry
(predominantly) of photocycloaddition reaction with weak interactions through cavitand-mediation
approach. The effectiveness of this method is demonstrated through the complete switch in regioselectivity
in some cases. In 2006 Ramamurthy et al (along with one of the authors of this manuscript) reported the
photoreaction of trans-cinnamic acids (CA) complexed within γ-cyclodextrin (γ-CD). The reaction yielded
the most compact syn Head-to-Head (syn H-H) dimer30 with excellent selectivities and high yields.
Considering the efficiency of this method, we envisioned that the cavitand-mediated photodimerization can
be further broadened to produce desired regioisomer. We reasoned that substituting the carboxylic acid
protons with alkyl group should disfavor the syn H-H arrangement, as the two alkyl groups would deter each
other sterically. This should favor the other compact, anti Head-to-Tail (anti H-H) dimer (figure 1). The work
reported herein is part of our ongoing effort35 to generalize the cavitand-mediated photodimerization
approach for directing reaction specificity to produce broad array of cyclobutanes. Our strategy towards this
goal involves modifying the intermolecular interactions between reacting alkenes, which will lead to a
different pre-orientation, and thus a different isomer. γ-CD-complexes of the alkenes reported in this were
irradiated as slurry, while earlier works were either performed in solid-state or aqueous solution. Thus, this
work is useful in understanding the stability of complex in slurry form. Cyclodextrins are used in drug
formulations as drug delivery agents. Hence, studying characteristics of complexes in slurry form will be
useful in this regard. We have also performed some comparative studies with another macrocyclic host 2-
hydroxy propyl γ-cyclodextrin (HP-γ-CD) to better understand supramolecular forces governing the relative
orientation of guests within cavitands.

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Favorable
π-π
interaction
Predominant complex structure
Unfavorable
steric interaction
minimized
Unfavorable
steric
interaction
R = H
Favorable
π-π
γ-CD, mol. wt: 1297.15 g/mol
interaction
R = H or *-CH2-CH(OH)CH3
2-HP-γ-CD, mol. wt:1587 g/mol
Complex structure increasingly
favoured as size of
increases
Figure 1. Graphical representation of the supramolecular approach used to switch the relative orientation of alkenes within the
cavitand to direct regioselectivity.
EXPERIMENTAL
γ-Cyclodextrin was purchased from CDT, Inc. and used as received. 2-hydroxypropyl-γ-
cyclodextrin was purchased from Research Biochemicals International. The cinnamic acids, solvents, and
drying agents were purchased from commercial sources (Sigma Aldrich, Fischer Scientific, VWR, and MP
Biomedicals LLC) and used as received.
Preparation of esters: Cinnamic acids purchased from commercial vendors were converted to the
respective acid chlorides by refluxing in excess thionyl chloride. The excess thionyl chloride was removed
under vacuum and the dry product was refluxed in excess alcohol. The reaction mixture was washed with
water, and aq. sodium carbonate to remove water-soluble components, and extracted with
dichloromethane. Unreacted acid/acid chloride were simply removed in the base wash. The organic layer
was stripped off the solvent using a rotavap, dried under high vacuum for several hours, and analyzed using
1H NMR. Esters prepared this way yielded products in almost 100% purity, and were obtained as viscous
neat substances. The vacuum dried products were used to prepare standard solutions in volumetric flasks
in dichloromethane. Aliquots of the solutions for required quantities were measured out into 20 mL
scintillation vials, dried using nitrogen stream to remove the solvent, and mixed with 0.5 (or 1) equivalents
of host for complexation.
Complexes and irradiation: Host-guest complexes were prepared by mixing half equivalents of γ-
CD with the nitrogen stream-dried ester with 5 mL of water. The mixtures were sonicated for 2 hrs, followed
by 5 hrs of stirring. A white precipitate formed during sonication indicating complexation. Resulting insoluble
white precipitates were irradiated as it is in slurry form. Irradiations were performed with a medium pressure
mercury vapor lamp immersed in a water-cooled Pyrex jacket. Following irradiation, the inclusion
complexes were dissociated through biphasic extraction with water and ethyl acetate. The organic layer
was separated, and residual water was removed using anhydrous Na2SO4. The solvent was rotary
1
evaporated, and the final sample dried under high-vacuum. The dried samples were then subject to H
NMR (300 MHz Bruker Avance) analysis in CDCl3. Product proportions were determined from integration
of peak areas of characteristics signals. Integrations, and coupling constants were performed using the
Bruker Topspin software, and ACD labs freeware respectively. The dimer signals were characterized based
on NMR data reported in literature.16, 18, 29, 40-44 In cases of esters with more than 2-carbon alkoxy groups,
the reaction mixtures were too complex for direct NMR analysis. The dimers were base hydrolyzed, and

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acid treated to obtain the dimers in their carboxylic acid forms. The dimers with carboxylic acid units were
then compared with the literature-reported chemical shifts.
Computational chemistry calculations were performed using the Gaussian ’09 software package.45,
Geometry optimizations and thermochemical calculations of the complexes were performed using the
46
Universal Force Field package in the software (molecular mechanics). Both the geometry optimizations and
thermochemical calculations were performed in water as the medium based on the Implicit Polarizable
Continuum Model (IPCM).
RESULTS AND DISCUSSION
Host, guests, and complexes: Cyclodextrins are a family of toroid-shaped macrocyclic cavitands
composed of oligomeric sugar (glucose) units. They are made from the enzymatic digestion of starch to
produce predominantly α-, β-, and γ-cyclodextrins. These cavitands consist of hydroxyl groups on the top
and bottom rims rendering them water-soluble, while the interiors are hydrophobic, which can
accommodate hydrophobic small molecules within. γ-cyclodextrin consists of eight glucose units and is the
larger among the three, capable of including two guests simultaneously. The choice of γ-CD for this study
is based on its tendency to form ternary complexes, which will be conducive for the bimolecular
photodimerization reaction. The cavitands used in this γ-CD, and its functionalized derivative (2-
hydroxypropyl- γ-CD) were purchased from commercial vendors (experimental section). Cinnamic acids
are naturally occurring compounds found commonly in plants, and are well-studied photosubstrates in
organic photochemistry. Excited state reactivity of cinnamic acids predominantly favors isomerization over
photodimerization due to entropic disfavorability for the latter pathway. Some of the stereoisomers of
cinnamic acid photodimers (truxillic and truxinic acids) are also found naturally in plants. Efficiency of
cinnamic acid photodimerization is improved when two cinnamic acids are placed proximally, such as in
solid-state or host-guest complexes. In this paper we have used γ-CD to bring two cinnamic acids/esters
together to control dimer stereoselectivity by taking advantage of the steric and electronic interaction
between them. Esters used in this study were synthesized by treating the cinnamic acids with thionyl
chloride to generate acid chlorides followed by alcohol solvolysis reaction.
Photochemical studies: We started our investigation with the reaction of 1:2 complex of γ-CD cinnamic
acid complex. When irradiated as a slurry, the complex yielded predominantly syn H-H dimer (83%) and a
small amount of cis-cinnamic acid (figure 2, and table 1). This is similar to the reaction reported by
Ramamurthy’s group in 2006, in the solid state.26 The predominance of dimer in product mixture is attributed
to predominance of 1:2 complex, with alkenes in proximity. As in this reaction, the cis cinnamic isomer was
not formed in any significant amounts in other reactions as well (vide infra).The high degree of reaction
control is very similar to that of reactions in solid-state. Among the four possible dimers that could result
from this reaction, only syn H-H was the major product at near complete conversion. This suggests that the
overlapping phenyl ring precursor (syn H-H) arrangement is more favourable. Though the compactness of
the resulting dimer was originally thought to be the main reason for the selectivity, we speculate that the π-
π interaction between the aromatic rings is also a dominant stabilizing factor favouring the precursor syn
H-H arrangement. Support for this speculation can be derived from related work in literature,22, 29, 41, 47, 48
where stereoisomers with stacked aromatic rings were major products.
We then proceeded to study alkyl cinnamates. The steric interaction between alkyl groups should
disfavor the H-H arrangement, leading to another compact arrangement (head-to-tail) that could fit within
the γ-CD cavity. Such a reasoning proved to correct from the product distribution observed in the reaction
of 1:2 complex of γ-CD-trans methyl cinnamate complex. As shown in figure 2 (second 1H NMR spectrum),
we observed the formation of two dimeric products as the major products of the reaction with almost no
isomerization. Based on the shape, multiplicity, chemical shifts, and coupling constants, the products were
identified to be syn H-H and anti H-T dimers. The dimers formed in approximately equal proportions with
slight excess of the anti H-T isomer. Intrigued by these findings, we proceeded to perform a systematic

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study to understand how the characteristics of alkyl substituents influence complex structure, and dimer
distribution.
Irradiation of 1:2 complex of trans-ethyl cinnamate swayed the selectivity more towards the anti H-
T dimer (63%), expectedly due to further destabilization of the H-H arrangement induced by the ethyl group.
Finally, with isopropyl cinnamate we observed that the reaction yielded the anti H-T dimer exclusively. This
reaction outcome marked a complete switch in regioselectivity from syn H-H to anti H-T. Gradual change
from formation of predominance of one dimer to the exclusive formation of the other is presented in figure
2.
Table 1. Product distribution resulting from irradiation of trans cinnamic acid and alkyl cinnamates complexed to γ-CD.
Cinnamic
acid (R2-Ar)
Alkoxy group
(R1-O)
% syn H-H
% anti H-T
% syn H-T/anti H-H
cis
H
H
1
83
-
-
-
17
H
H
H
H
H
H
methyl
Ethyl
isopropyl
n-propyl
n-butyl
1a
1b
1c
1d
1e
1f
45
34
-
26
16
-
52
63
97
47
17
-
-
-
-
10
11
-
3
3
3
17
56
100
cyclohexyl
Percentage of products from reaction mixtures calculated from integration of 1H NMR signals.
Table 1 consolidates the product distribution resulting from irradiation of 1:2 γ-CD complexes of
alkyl cinnamates. The isopropyl group conferred high degree of reaction control and selectivity, as anti H-
T was the only product observed. But, switching the isopropyl group to n-propyl group resulted in some
noticeable differences, though anti H-T was still the major product. Significant amounts of two other dimers,
and cis cinnamate were observed in the NMR spectrum. One of those dimers was the syn H-H dimer, and
based on the signal structure, the other is speculated to be anti H-H. However, the identity of the dimer is
not crucial due to its lower proportion, and we merely consider the formation of this dimer as an indication
of loss of reaction control. This loss of reaction control was even more evident with n-butyl cinnamate,
where cis cinnamate was the major product. The end-point of the trend was found in cyclohexyl cinnamate,
for which isomerization product was the only photoproduct, and no dimerization product resulted. We
believe that the larger size of the cyclohexyl group prevented the guests from forming a 1:2 complex, and
that 1:1 complex is most likely the predominant complex.
Table 2. Product distribution resulting from irradiation of substituted trans cinnamic acid and alkyl cinnamates complexed to γ-CD.
Cinnamic acid
(R2-Ar)
Alkoxy group
(R1-O)
% syn H-H
% anti H-T
% syn H-T/anti H-H
% cis
4-methyl
4-methyl
4-methyl
methyl
Ethyl
isopropyl
2a
2b
2c
43
28
20
51
64
77
-
-
-
6
8
3
3-methoxy
3-methoxy
Methyl
Isopropyl
3a
3b
61
24
32
58
-
7
7
11
Percentage of products from reaction mixtures calculated from integration of 1H NMR signals.
Having studied the influence of size of the alkyl group on product distribution, and its correlation to
complex structure, we turned our attention to understanding the influence of substituents on the aromatic
side of the guest. Alkyl cinnamates with methyl, methoxy, and halogen substituents on the aromatic ring
were studied. Product mixtures from photochemistry of complexes of esters of 4-methyl cinnamic acid40 (2)
followed a similar selectivity trend as those for the parent cinnamates, discussed above; amount of anti H-
T in reaction mixture increased with increasing size of alkoxy group. We noticed that despite the presence
of volume-demanding methyl substitution on the aromatic ring, methyl and ethyl esters of the acids (2a-b,
and 1a-b) yielded similar proportions of the two dimers. It is important to point out here that 4-methyl
cinnamic acid yielded syn H-H dimer selectively in solid-state.26 Hence, it is not surprising that the methyl
and ethyl esters of 1 and 2 behave similarly. Isopropyl ester of 2 yielded anti H-T as the predominant
product. However, a 20% of syn H-H also resulted in the reaction, which was not observed for 1C. We

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believe that this is difference is due to the larger size of isopropyl group and the steric conflict it poses is
with aromatic methyl group is now significant. This should have reduced the difference in stabilization
energies between the H-H and the H-T arrangements. Such an effect would be missing in 1C, which will
lead to a larger difference in energies between the two arrangements. This line of reasoning was justified
by similar product distributions for 3-methoxy cinnamates (3a-b) wherein the isopropyl ester afforded anti
H-T as the major product with sizable amount of syn H-H. However, a greater loss in reaction control was
also recognized due to formation of noticeable amount of a third dimer, and isomerization product.
Figure 2: 1H NMR spectra of reaction mixtures that resulted from the irradiation of slurry 1:2 (H:G) γ-CD complexes of cinnamic acid,
and its esters. A gradual, but complete, switch from syn H-H to the anti H-T dimer was achieved through the use of appropriate alkoxy
substituent.
Halogen-substituted cinnamates afforded a more different product distribution, and interesting
insight into the halogen…halogen interactions. Halogen…halogen interaction49-52 (C-X…X-C) is an
important, yet relatively less-studied, bonding interaction, and is known to be attractive in nature. For
example, Cl…Cl attractive forces have been used in crystal engineering to direct molecular packing into
arrangements where the chlorines are proximal, or oriented towards to each other.53-56 Given this
background, we expected that chloro cinnamates (4a-d) will yield more H-H dimers than the corresponding
unsubstituted cinnamates 1a-d. As predicted, methyl ester complex (4a) yielded a much higher percent of
syn H-H57 (67%) than 1a (51%). Correspondingly, a significantly lower percentage of anti H-T dimer was
seen, along with similar proportion of a third dimer. Based on the chemical shift and peak shape the third
dimer was identified to be the anti H-H isomer (supporting information, isopropyl ester). The effect of Cl…Cl
in favoring H-H arrangement is evident from this first example. We then investigated chloro cinnamates
with larger alkoxy groups (4b-d). Despite the increase in size of alkoxy group in 4b-d, syn H-H was the
major product in chloro cinnamate reactions. This is markedly different from what was observed earlier as
the steric conflict between the alkoxy groups favored the H-T dimer more. The combined proportion of the
H-H dimers indicate a strong attractive force between the intermolecular chlorine atoms, which is able to
overcome the steric conflict between the isopropyl groups. The magnitude of Cl…Cl interaction can be
qualitatively understood by comparing the relative proportions of the H-H and the H-T dimers between

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esters with same alkoxy group. While the isopropyl cinnamate yielded 100% H-T dimer, the isopropoxy
ester of chloro-substituted cinnamic acid yielded around 70% H-H dimers. One might wonder whether a
steric interaction from chlorine substitution on aromatic ring could destabilize the H-T arrangement, leading
to higher proportion of H-H dimer. However, 3b with its bulky methoxy substitution was able to afford no
more than 24% syn H-H dimer, while the methoxy group is bulkier than a chloro atom. The difference of
around 50% of H-H dimers between 4d and 3b can be attributed to the Cl…Cl interaction.
Table 3. Product distribution resulting from irradiation of halogen-substituted trans cinnamic acid and alkyl cinnamates complexed to
γ-CD.
Cinnamic
acid (R2-Ar)
Alkoxy group
(R1-O)
% syn H-H
% anti H-T
% syn H-T/anti H-H
% cis
2-chloro
2-chloro
2-chloro
2-chloro
3-bromo
3-bromo
3-fluoro
Methyl
Ethyl
n-propyl
isopropyl
Methyl
4a
4b
4c
4d
5a
5b
6a
69
52
35
52
35
60
-
10
12
26
29
57
9
22
25
19
-
12
14
14
-
8
-
Isopropyl
Isopropyl
40
100
-
-
-
Percentage of products from reaction mixtures calculated from integration of 1H NMR signals.
The Br…Br and F…F interactions were explored through compounds 5-6. The esters of bromo
cinnammic acids yielded high amounts of syn H-H dimers42 as well (figure 3), though it was slightly lesser
in proportion than the corresponding chloro compounds. This observation in combination with the product
distribution observed for 4d reinforces the influence of attractive halo…halo interaction in selectivity.
However, no significant amount of the third dimer was seen. Thus, here we see that despite the presence
of a bulky alkoxy substitution, the halo…halo attraction is able to direct intermolecular orientation towards
the H-H arrangement. On the other hand, isopropyl ester of fluoro cinnamic acid did not yield any H-H
dimer44 at all, and anti H-T was the only product. Based on this we believe that the strength of F…F
interaction is almost incomparable to that of the larger halogens. The directing effect of the halogen effect
is summarized with the NMRs in figure 3. Considering the structure of the complexes (vide infra) and the
predcited co-planar relative arrangement of the guests within the cavitand, it is expected that the C-X…X-
C contact angle would be around 90°, which is not unusual for halogen…halogen interactions.18, 49
Figure 3. 1H NMR spectra of reaction mixtures that resulted from the irradiation of slurry 1:2 (H:G) γ-CD complexes of isopropyl esters
of halo cinnamic acid. The difference in selectivity are attributed to the halogen…halogen interaction (or lack thereof).
Time-dependence and stoichiometry studies: The premise of this project is to deduce complex structure,
and relative orientation of the alkenes based on stereochemistry of the dimer. Thus, it is important to ensure
that product selectivity observed in the reactions is not due to (a) differential reactivity and/or (b) lack of
product representation from non-reacting orientations. Towards this end, we performed time-dependence

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experiments scanning a broad conversion range. We chose to study the methyl cinnamate γ-CD complex
(1:2) as a representative example as it is yields both the dimers. A slurry of the complex was split evenly
into four equal portions, and irradiated for four different durations: 1, 3, 7, and 9 hours. Any difference in
product selectivity between the reactions could indicate differential reactivity. The proportion of syn H-H
and the anti H-T dimers remained almost constant throughout the four reactions (supporting information).
The variation in dimer proportion was within 5%, which should be considered the margin of error. Except
for the difference in intensity of the trans ester signals, the product proportions were essentially constant.
Thus, the reaction selectivity is representative of the complex structures in the bulk of the slurry.
It is clear that the large cavity of γ-CD forms the ternary 1:2 complex. However this does not
necessarily imply that 1:2 complex is the only stable complex, as we did not have more host to form other
complex ratios. Hence, we performed stoichiometry experiment to understand the dynamics between host
and guest, variation in complex stoichiometry and structure. Methyl cinnamate and isopropyl ester of 4-
methyl cinnammic acid were used as representative examples. As mentioned earlier, irradiation of complex
resulting from mixture of 1:2 complex of 1a yielded roughly equal proportions of syn H-H and anti H-T
dimers. Similarly, the 1:2 complex of 2c yielded about 80% anti H-T and 20% syn H-H. We then studied
reactions of host-guest ratio was increased to 1:1. Product mixtures resulting from the 1:1 complexes of 1a,
and 2c were both surprisingly very similar to the product mixtures from the 1:2 complexes. This suggests
that in the slurry even when 1 equivalent of the host was present, photodimerization was the major reaction
pathway, implying that the 1:2 complex is much more stable than 1:1. This might appear counter intuitive,
as the steric interaction from dual occupancy will be destabilizing. But, the predominance of 1:2 complex
despite excess γ-CD could be explained based on concept of ‘tight fit’, wherein a stable complex results
between cavitand and guest of complementary sizes, than with a guest of smaller size. Alternatively, one
might wonder whether the stability of the 1:2 complex could also be due to the stabilizing π-π (maybe even
CH-π) interaction(s). Computational studies we performed (discussed below) correctly predicted that a
ternary complex will be more stable than the binary complex. As the computational method we used (MM)
does not involve electronic interaction term, and it was able to correctly predict stabilities, we believe that
the tight-fit factor is a more plausible explanation.
2-hydroxypropyl-γ-cyclodextrin complexes: One of our approaches for generalizing the cavitand-
mediation method to produce stereospecific cyclobutane structures is to explore the influence of cavitand
characteristics on reaction selectivity. We intend to study the influence of other cavitands on selectivity.
This would include cavitand families such as cucurbiturils, and calixarenes, and their derivatives. As a
preliminary effort, we have studied reactions of some cinnamates within 2-hydroxypropyl-γ-cyclodextrin
(2HP-γ-CD). 2HP-γ-CD is a functionalized derivative of γ-CD, wherein some of hydroxyl groups are
randomly substituted with 1-(2-hydroxy)propyl units. The degree of substitution is approximately five
hydroxypropyl units per cavitand. The presence of the hydroxypropyl arm extends the portal height with
solubility comparable to that of γ-CD in aqueous medium. Complexes of 2-HP-γ-CD were prepared in an
identical manner to that of γ-CD complexes. However, visually, the amount of precipitate resulting from the
complexation was significantly lesser.
Irradiation of 2-HP-γ-CD complex of cinnamic acid resulted in high, selective yield of the syn H-H
dimer, which was similar to that of the parent cavitand (table 4). On the other hand, methyl cinnamate
yielded higher amount of syn H-H dimer, and isomerization product than the γ-CD complex. A marked
difference was observed in case of the isopropyl ester, where the 2-HP-γ-CD complex yielded no dimers
at all, and cis methyl cinnamate was the only product observed. The presence of bulky alkoxy substitution
on the tail-end of guests most likely face a steric interaction from the 2-hydroxypropyl groups in 2-HP-γ-CD,
leading to formation of higher proportion of 1:1 complex, which results in isomerization. These reactions
suggest that 2-HP-γ-CD is not a conducive host for photodimerization larger guests. The hydroxypropyl
arms, even though present in small numbers, are strong enough to prevent formation of higher order
complexes.

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Table 4. Product distribution resulting from irradiation of substituted trans cinnamic acid and alkyl cinnamates complexed to 2-
hydroxypropyl-γ-CD.
Cinnamic acid
(R1-Ar)
Alkoxy group
(R2-O)
% syn H-H
% anti H-T
% syn H-T/anti H-H
% cis
H
H
H
H
1
87
48
-
-
26
-
-
-
-
-
-
-
-
-
-
13
26
Methyl
Isopropyl
1a
1c
1c
3
2a
2c
100a
100b
8
-
3-Methoxy
4-Methyl
4-Methyl
H
92
35
-
Methyl
Isopropyl
20
-
45
100
aComplex stoichiometry (1:2, host:guest) bcomplex stoichiometry (1:1, host:guest). Percentage of products from reaction mixtures calculated
from integration of 1H NMR signals.
Computational studies: Computational studies were performed to understand the structural
characteristics of the complexes involved in this work. Structures of individual molecules, their γ-CD
complexes, and their binding energies in polar medium in universal force field (UFF) were calculated in
Gaussian ’09. We included water as the solvent in our calculation as hydrophobic interaction is the primary
force driving complexation. Solvent effects due to aqueous environment was included through the use of
implicit polarizable continuum model (IPCM).
(eq. 1)
(eq. 2)
ΔE = Ecomplex – (ECD + Eguest1 + Eguest2
)
Δ Δ E = ΔEcomplex(syn H-T) – ΔEcomplex(anti H-T)
Figure 4. Energy minimized structures (MM-UFF) of 1:2 host-guest complex of methyl cinnamate with γ-CD, and their stabilization
energies. Hydrogens are not displayed for sake of clarity. Note: Two isomeric complex structures of syn H-H arrangement are possible, which arise from
carboxylic acids protruding out of the secondary portal or the primary portal. Analysis of the two isomeric structures of cinnamic acid complexes show that the former is more
stable (supporting information). In this study we have focused only on syn H-H structures where the carboxylate units protrude through the secondary portal.
Generally AMBER force field is used to study organic molecules, while UFF is applicable to
molecules containing any element in the periodic table. However, UFF treatment of organic molecules,58
inclusion complexes of organic59, 60 and metal ion complexes61, 62 can be found in literature.63, 64 We intend
to study these complexes and future complexes using AMBER force field in future and compare the
predictabilities of UFF and AMBER. Relative stabilities of the complexes were deduced through the
differences in formation energies of complexes and those of the guests, as expressed in equation 1.
Computational analysis of supramolecular assemblies is a relatively recent endeavor among
supramolecular chemists. Dodzuik, an expert in the field, argues that stand-alone computational studies of
host-guest complexes cannot yield realistic information regarding the complexes,65 and that reliable

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conclusions can only be elicited with the help of a comprehensive and systematic analysis of a given
system. We agree with her conclusions derived based on critical analysis of previously published works,
discussed in her book. Thus, instead of exploring the structures from a purely computational standpoint,
we believe that computational studies combined with experimental data can useful in providing qualitative
information regarding host-guest complexes, and help in visualization of complex structures. Our aim for
using computational chemistry in this work was to explore possible correlation between theoretical and
experimental findings, and understand relative stabilities of complexes in a qualitative manner.
Figure 5. Energy minimized (MM-UFF) structures of 1:1 host-guest complexe methyl cinnamate with γ-CD. Hydrogens omitted for
clarity
We primarily studied the structures of complexes with the alkenes in the syn H-H and anti H-T
precursor arrangements, as the corresponding dimers were the major products observed. Moreover,
optimization of complexes with other two precursor arrangements resulted in structures in which one of the
alkene bonds were much farther away. Geometry optimized structures of the complexes along with their
stabilization enthalpies and free energies (standard conditions) are presented in figures 4-7. It should be
noted that the numerical values of individual energies are rather less significant, but the difference in
stabilization energies between two different complexes can be considered as useful information (eq. 1 and
2). The enthalpic and free energy changes for complexes of 1a (figure 4) and 1c (figure 5) with γ-CD for
both the anti H-T and syn H-H arrangement were all negative values, suggesting an enthalpy driven
spontaneous process. Comparing the corresponding enthalpic and free energy values between the two
complexes (different arrangements) of 1a indicate that the syn H-H arrangement is enthalpically more stable
by 1.1447 kcal/mol, while the anti H-T is more stable by 0.0554 kcal/mol free energy wise (figure 4). The
values for the complexes of isopropyl ester 1C show that the anti H-T dimer is more stable both enthalpy
(2.115 kcal/mol) and free energy wise (2.409 kcal/mol) (figure 5). The stabilization of the anti H-T, compared
to the syn H-H arrangement, was significantly greater for the isopropyl ester (-2.409 kcal/mol) than the
methyl ester (-0.0554 kcal/mol). This trend in stabilization energy increase concurs with the experimental
result where methyl cinnamate yielded roughly equal amounts of the syn H-H and anti H-T dimers, while
the isopropyl ester yielded exclusively the latter.

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Figure 6. Energy minimized structures (MM-UFF) of 1:2 host-guest complexes of isopropyl cinnamate with γ-CD, and their stabilization
energies. Hydrogens are not displayed for sake of clarity.
Computational results for the complexes of parent cinnamic acid 1 (figure 6) predicted that the anti
H-T arrangement is be more stable than the syn H-H by 0.550 kcal/mol (ΔH), and 3.361 kcal/mol (ΔG).
According to this prediction, the anti H-T dimer should be the major product, contrary to the syn H-H dimer
observed experimentally. The contradiction here arises due to the lack of attractive electronic terms (in this
case π-π interaction) in molecular mechanics force field definitions, which does not account in such
stabilization in syn H-H. Thus, the pure MM treatment based on hydrophobic and steric interactions would
predict that the H-T arrangement would be more stable due to the missing phenyl-phenyl steric conflict.
This, in fact, serves to support the idea that though π-π interaction is a weak attractive force in nature, it
can profoundly manifest in chemical reactions when mediated though macrocyclic hosts.
Figure 7. Energy minimized structures (MM-UFF) of 1:2 host-guest complexes cinnamic acid with γ-CD, and their stabilization
energies. Hydrogens are not displayed for sake of clarity.
In our computational studies, we also studied the 1:1 complex of methyl cinnamate (figure 7). The
enthalpic and free energy stabilizations for the complexes were calculated to be -16.506 kcal/mol and -

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4.178 kcal/mol. Comparing these values with that for the 1:2 complex (-36.027 kcal/mol, and -19.708
kcal/mol, figure 4), it follows that the 1:2 complex is more stable than the 1:1 complex. This is also consistent
with the experimental observation that 1:2 complex is preferentially formed over the 1:1 complex, even
when equimolar amounts of the host and guest were mixed. Thus, based on the above results, we believe
that UFF is able to predict the relative stabilities of complexes.
CONCLUSION
In this work, we have shown regioselectivity of photocycloaddition between cinnamic acids and
their esters can be directed through the use of non-covalent interactions. The reactions were also affected
in a stereoselective manner. Cinnamic acid yields syn Head-to-Head (syn H-H) as the only dimeric product
when irradiated as a complex in γ-cyclodextrin. Our investigations lead us to believe that π- π interaction
is an important factor in its selectivity. The selectivity is completely reversed when isopropyl cinnamate- γ-
cyclodextrin complex was irradiated, resulting in the anti Head-to-Tail (anti H-T) dimer exclusively, as steric
interaction between the isopropyl groups favor a H-T arrangement in complex. This complete switch in
regioselectivity marks the next step in our effort to generalize the cavitand-mediated photodimerization
approach to produce broad array of substituted cyclobutanes. Cinnamic acid esters with smaller than butyl
groups bind with the macrocyclic cavitand γ-cyclodextrin to form 1:2 (host:guest), and yield photodimers
predominantly. The relative proportion of the syn H-H and anti H-T dimers is influenced by the size of alkoxy
chain, as the latter was favored with larger alkoxy groups. This gradual shift in product distribution can be
regarded as tunable control in reaction selectivity. Stoichiometry experiments suggest that 1:2 (host:guest)
complex is more stable than the 1:1 complex, perhaps due to the tight-fit factor.
The effect of halogen substituents on the aromatic ring was also studied. Chloro and bromo
substituted cinnamate esters yielded significantly higher syn H-H in their product mixtures than the other
potosubstrates due to the attractive halogen…halogen interaction. Product distributions indicate that the
chlorine…chlorine and bromine…bromine interaction is rather strong, and outweighed the destabilization
from steric conflict between even isopropoxy groups. Fluorine…Fluorine interaction appears to be very
weak in comparison. Computational studies of the complexes were performed to explore its predictive
power. Relative stabilities of complexes predicted using Molecular Mechanics Universal Force Field (MM-
UFF) analysis of the complexes in an aqueous shell is consistent with structures deduced using
photochemical studies. Our future efforts will aim to access the other photodimers (anti Head-to-Head and
syn Head-to-Tail), and non-symmetric cyclobutanes as well with the cavitand photodimerization approach.
We believe that this method will also serve as a means to understand the dynamics and relative influences
of supramolecular interaction in host-guest complexes.
Acknowledgements
Acknowledgment is made to the Donors of the American Chemical Society Petroleum Research
Fund (#54862-UR4) for support of this research. MP thanks the office for undergraduate research and
creative for its financial support. The authors acknowledge thank UNK undergraduate students Mallory
Breems, and Jessica Lynn Hoffert for their help with some experiments.
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Graphical Abstract
Table of content entry
A cavitand mediation approach involving host-guest and guest-guest interactions has been developed to
direct regioselective photocycloaddition of non-symmetric alkenes wherein a complete reversal in
selectivity is achievable